"While past attempts to use immunotherapy have failed to dramatically shift the paradigm of care for the treatment of patients with sarcoma, a great opportunity now exists to increase the therapeutic options available in this challenging group of diseases."

"Most of the immune-based therapies studied to date have been well tolerated, and some have shown promise in the setting of refractory or high-risk malignancies, demonstrating that immunotherapy has the potential to overcome resistance to conventional chemotherapy."

Immunotherapy for Sarcomas

What is immunotherapy and what role does it play in cancer treatment?

Immunotherapy, which is also called biological therapy or biotherapy, is a treatment that uses certain characteristics of the body’s immune system to fight disease. As we will see later, the basic idea of cancer immunotherapy is to try to get the immune system to react to the tumor’s cancer cells as if they are foreign. The use of immunotherapy as a cancer treatment is not new. Dr. Herberman notes that, "For over 100 years, immunologists have been intrigued by the concept that tumor cells are foreign to the local host and that the immune response has the potential to recognize the key difference(s) and reject the tumor cells."1 Drs. Brown and Kirkwood point out that immunology has, "burgeoned from the esoteric specialty of a small body of individuals into an immense academic discipline whose basic doctrines permeate all aspects of clinical medicine."2 Although immunotherapy is sometimes used by itself, it is typically used as an adjuvant to another primary therapy, i.e., along with or after the primary therapy, to add to the anticancer effects of the primary therapy.

The Immune System

The immune system defends the body against infection, disease and foreign substances. It is made up of many organs and cells. An antigen is a substance that causes the immune system to make a specific response, called the immune response. Viruses, bacteria, germs, and parasites contain substances that are not normally present in the body and thus cause an immune response. The immune response can lead to destruction of the antigen and anything it is part of or to which it is attached.

Several different types of cells are involved in the immune system’s response to an antigen. Among the cells are antigen-presenting cells (APCs), lymphocytes, and granulocytes. Among the APCs are monocytes and macrophages and dendritic cells. Among the lymphocytes cells are B cells (B lymphocytes), T cells (T lymphocytes), Killer T cells, and Helper T cells.

Vaccine Therapy and Antibody Therapy

Cancer cells have substances on their outer surfaces that can act as antigens and thus "mark" the cells as different or abnormal. Viruses, bacteria, and parasites have cells that are substantially different from normal human cells because they are truly foreign to the body and are detected by the immune system. However, the differences between cancer cells and normal human cells may be more difficult for the immune system to detect. Cancer immunotherapies are designed to help the immune system recognize cancer cells and/or to strengthen the immune response to the cancer cells and thus destroy the cancer. The cancer cells' antigens may not be different enough from those of normal cells to cause an immune reaction; thus, the immune system may not recognize the cancer cells as foreign. The immune system may recognize the cancer cells’ antigens, but the immune response may not be strong enough to destroy the cancer. Additionally, some cancer cells themselves may also give off substances that prevent the immune system from responding properly.

There are two broad classes of immunotherapies, active immunotherapy and passive immunotherapy. Active immunotherapies stimulate the body’s own immune system to fight the disease. Passive immunotherapies do not rely on the immune system to attack the disease; instead, they use immune system components (such as antibodies) that are created outside of the body to fight the disease. These two approaches are also called vaccine therapy and antibody therapy respectively. In vaccine therapy, or active therapy, the patient is given a vaccine that should stimulate the immune system to attack the cancer. In antibody therapy, or passive therapy, the patient is given antibodies that will hopefully target the cancer but leave the non-cancerous cells alone. The problem with both approaches is finding substances that the immune system can target (antigens) which are only present on the cancer cells and not on normal cells. Sometimes vaccines combined with nonspecific immunotherapy, using additional substances or cells called adjuvants in order to boost the immune system’s response. Doctors may employ two or more of these immunotherapy options together.

An antibody is a protein made by certain white blood cells in response to the presence of an antigen. Antibodies bind to antigens to help destroy the antigen. Each antibody can only bind to a specific antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for other cells to destroy the antigen.

Vaccine Therapy

Cancer vaccines contain cancer cells, parts of cells, or pure antigens that increase the immune response against cancer cells that are already present in the body. They are considered active immunotherapies since they are meant to trigger your own immune system to respond. They are considered specific because they do not result in a generalized immune system response. They cause the immune system to produce antibodies to one or several specific antigens, and/or to produce Killer T cells to attack cancer cells that have specific antigens.

There are several different types of vaccines; among them are tumor cell vaccines, dendritic cell vaccines, antigen vaccines, anti-idiotype vaccines, and DNA vaccines. I will only briefly discuss tumor cell vaccines in Q&A response column. Tumor cell vaccines use cancer cells that are removed from the patient during surgery. The tumor cells are then killed so they cannot form more tumors. The tumor cells may be modified with chemicals or genes, or mixed with other substances known to increase the immune response in an attempt to improve the effectiveness of the vaccine. The tumor cells are the injected back into the patient. The antigens on the cells are recognized and attacked by the immune system.

The two basic types of tumor cell vaccines are autologous and allogeneic. An autologous vaccine is made from tumor cells taken from the patient that will receive them. An allogeneic vaccine uses cells of a particular cancer type that originally came from someone other than the patient that will receive them. The cells are often "grown" in a lab from a "stock" of cancer cells kept for this purpose.

There are several problems with tumor cell vaccines:

the difficulty and cost of creating a new, unique vaccine for each cancer patient

the mutations (changes) in the cancer cells can result in the vaccine becoming less effective over time

When cancer metastasizes, the new tumor sites can have cells with slightly different antigens; thus a vaccine made from one tumor site might not be effective against the other tumor sites.

There are many vaccine-based clinical trials underway for a wide variety of cancers, including sarcomas. Some of them are currently recruiting patients and can be viewed here.

Antibody Therapy

In monoclonal antibody therapy, large quantities of antibodies are produced in the lab outside the body rather than inside the body by the immune system. Since the immune system does not take an "active" role in fighting the cancer in antibody therapy, it can be used even in patients with a weakened immune system. Researchers can make monoclonal antibodies that react with specific antigens on certain types of cancer cells. As researchers discover more specific cancer-associated antigens, they will be able to direct monoclonal antibodies against more and more cancers.

Monoclonal antibodies are laboratory-produced antibodies that can locate and bind to specific cancer cells anywhere in the body. Each monoclonal antibody recognizes a different protein on specific cancer cells. Monoclonal antibodies are used in cancer detection as well as in cancer therapy. They can be used alone or to deliver drugs, toxins, or radioactive material directly to a tumor.

There are two types of monoclonal antibodies that are used in cancer treatments:

Monoclonal antibodies without any drug or radioactive material attached to them: These are referred to as "naked" monoclonal antibodies. Naked antibodies attach themselves to specific antigens on cancer cells.

Monoclonal antibodies joined to a chemotherapy drug, radioactive particle, or a toxin (a substance that poisons cells): These are referred to as "conjugated", "tagged," "labeled," or "loaded" monoclonal antibodies.

There are clinical trials of monoclonal antibodies in progress for a wide range of cancers, including non-Hodgkin’s lymphoma, breast cancer, acute myelogenous leukemia, chronic lymphocytic leukemia, colorectal cancer and sarcomas. Researchers at St. Jude Children’s Research Hospital and other institutions are studying a drug called Herceptin® to treat recurrent or metastasized osteosarcoma. In this clinical trial, Herceptin® is given by vein. Some of the current monoclonal antibodies being studied in conjunction with sarcomas are: MAb, AME, Onyvax-105, bevacizumab, and trastuzumab. Another, TriGem, has demonstrated the ability to induce an immune response to the GD2 ganglioside. This is an antigen that is present on a number of tumor types, among them are melanoma, small cell lung cancer, neuroblastoma and sarcoma. To view open clinical trials that involve monoclonal antibodies, click here.

(2) Immunotherapy of Cancer, by Dr. C. Komen Brown and Dr. John Kirkwood, Horizons in Cancer Therapeutics™: From Bench to Bedside, Vol. 2, No. 1, March 2001, pp. 3-25. Part of this article is devoted to an interesting discussion of significant events in cancer immunotherapy since 1870 and contains many useful figures to help the reader understand the underlying immunotherapy mechanisms. See our comments about Horizons in Cancer Therapeutics™ in the Odds and Ends section of this issue.

The Difficulty and Promise of Immunotherapy for Sarcomas

A Note from Dr. Letson, Coordinating Editor: This editorial focuses on the problems with immunotherapy in the treatment of sarcomas. Sarcomas are a very diverse group of tumors. In order to attack these tumors, researchers have used the science of adaptive immunotherapy to teach the immune system to develop a response to a specific target and develop an immune response. Dr. Bob Maki does an outstanding job pulling these concepts together and outlining the difficulties in immunotherapy in sarcomas.

The immune response can be harnessed to fight cancer. There are reports of spontaneous responses of kidney cancer and melanoma without intervention. These findings, as well as suggestions of less aggressive courses of melanoma in people who develop vitiligo, responses of melanoma to blockers of T cell immune inhibitor CTLA4, and the finding of better clinical outcomes with small cell lung cancer, ovarian cancer, and breast cancer in patients who develop autoimmunity against proteins found both in the tumor and the brain of patients, have given investigators tantalizing evidence that the immune response can be harnessed to fight cancer.

However, there are a number of problems regarding using the immune system against sarcoma. First, there are over 50 types of sarcoma, so what may work for one sarcoma "flavor" may not work for another. For similar reasons, it is difficult to identify proteins targets that may be of general usefulness for the treatment of sarcomas. Second, it is hard to monitor immune responses against most tumors. You can follow the blood for presence of antibodies or anti-tumor T cells (a type of white blood cell that attacks tumors), but is looking in the blood appropriate when so many T cells are in lymph node? Should we be looking at T cells in the tumor? If so, then patients would need many biopsies to find out if an immune therapy is working in the predicted manner. This is invasive, potentially painful, expensive, and thus very difficult to do.

One intriguing line of therapy regards cell surface molecules called gangliosides, a type of molecule built of special sugars (sialic acid) attached to fat molecules that then float in the membrane of the cell. It turns out that gangliosides are common in melanoma cells, but surprisingly even more common in several types of sarcomas examined. Thus gangliosides may serve as relatively tumor-specific approach to treat sarcomas. Research is soon to be underway in which several hospitals will look to vaccinate patients against gangliosides once lung metastases of sarcoma have been surgically removed, typically from the lungs, to see if one can prevent further recurrence by mounting an immune response, either using a non-specific immune stimulant, or using that same immune stimulant with gangliosides mixed in. Monitor the listings ClinicalTrials.gov as to the availability of this and other such vaccine studies. For example, studies in Japan are investigating whether vaccines against synovial sarcoma can be helpful in treating that form of metastatic sarcoma, and at the National Cancer Institute in the U.S. there has been an ongoing interest in vaccine therapy against sarcomas, in particular those that occur in children.

This vaccine study is tempered by the finding that in all, vaccines have benefited fewer than 5% of the people who have received them (for any type of cancer). Building on this concept, there is now an effort underway by Steven Rosenberg and his colleagues at NCI to use "adoptive immunotherapy" to treat synovial sarcoma. This involves taking T cells (a type of white blood cell) and teaching them to develop an attack against a protein called NY-ESO-1 that is found on synovial sarcoma tumor cells, on the ovary, and on the testis. Since one does not need the ovary or testis to survive, even if there were an immune response against these proteins in ovary or testis, it should not be life threatening. After 3-6 months, enough T cells are grown to attack the tumor in numbers far larger than anyone has been able to generate with tumor vaccines. If this approach is successful, it may set a new standard for immunotherapy trials, not just for sarcoma, but perhaps cancer in general.

The other way investigators are trying to harness the immune system is to provide extra signals to T cells and other immune cells that keep them active for longer, or that cause them to increase in number. These targets are called costimulatory molecules, and the first of these, with agents that recognize CTLA4, have been associated with people benefiting with melanoma and other cancers. Since there is a tremendous increase in the understanding of these sorts of molecules and how they interact in the immune system, this could, with vaccination, provide another robust approach to treating cancer with immune therapy. However, these compounds can be toxic, since they non-specifically turn on the immune system—so immune responses can develop against normal tissues such as the colon/intestines to cause diarrhea and "colitis" (inflammation in the colon) as well as rash from immune responses against the skin, and other side effects. The fine tuning of these responses will be a challenge for the next several years at least.

Thus, while some investigators are looking at new drugs to treat cancer, turning the immune system on in specific ways is an area of active research among many physicians and scientists, and as we have seen with advances in chemotherapy, we hopefully will see novel and effective therapeutics developed within the next few years to treat at least a subset of patients with sarcomas.